Extracellular signal transduction leading to specific gene expression is often carried out by a series of enzymatic reactions which ultimately modulate activity of nuclear transcription factors. In one such example, extracellular signaling alters cytoplasmic levels of adenosine 3',5'-monophosphate (cAMP) which in turn modulates levels of active cAMP-dependent protein kinase (PKA). Once activated, PKA migrates into the nucleus and phosphorylates transcription factors which recognize DNA sequences common to genes that are regulated by cAMP signaling pathways. The common DNA sequence which permits cAMP regulation of gene expression has been designated the cAMP regulatory element (CRE) and the transcription factors which recognize and bind to the CRE are known as CRE-binding (CREB) proteins. It has been proposed that CREB proteins are ordinarily found in association with CRE DNA sequences and that the phosphorylation state of CREB determines the degree to which the protein is capable of inducing transcription of the associated gene. Once phosphorylated, CREB is able to bind a CREB-binding protein (CBP) which permits interaction of the complex with transcription factor TFIIB.
It is therefore apparent that regulation of the phosphorylation state of CREB is central to specific gene expression by cAMP. The phosphorylation state of CREB, however, is not regulated solely by PKA. On the contrary, the degree of CREB phosphorylation is balanced between the activities of phophatases as well as kinases other than PKA. Thus, while CREB is a major participant in coordination of cAMP gene expression, CREB activity is subject to concurrent control by enzymes in other, non-cAMP related pathways.
Members in the CREB family of proteins contain conserved regions which carry out specific functions related to transcriptional activation. At the carboxy terminus, all CREB proteins have a leucine zipper region which permits dimerization of CREB with other CREB proteins or other heterologous transcription factor subunits. Adjacent the leucine zipper region, CREB proteins are characterized by a region designated the kinase inducible domain (KID) which is subject to phosphorylation by multiple kinases other than PKA, including for example, protein kinase C (PKC), casein kinase I (CKI) and casein kinase II (CKII), and possibly calcium-calmodulin dependent kinases I and II. At the amino terminus, CREB proteins each contain a DNA binding domain rich in basic amino acids. Despite seemingly subtle differences between proteins within the family, reports of variation in gene expression suggest that the proteins have unique physiological roles.